Project Summary/Abstract Many human diseases are characterized by dramatic changes in metabolism, an observation that is particularly evident in cancer, where rapidly proliferating cells become highly dependent on glucose metabolism. Cancer cells, however, do not use this increased glycolytic flux to generate energy but rather shuttle metabolic intermediates through biosynthetic pathways and eliminate excess pyruvate by producing lactate. This phenomenon, known as aerobic glycolysis or the Warburg effect, allows cancer cells to metabolize large quantities of glucose in order to generate the biomass required for cell growth and proliferation. The reliance of cancer cells on glucose metabolism suggests that this metabolic state could be exploited for therapeutic intervention, and has become a focal point in cancer research. I have discovered that the fruit fly Drosophila melanogaster also uses aerobic glycolysis to promote growth, and have established Drosophila as a model system for studying the genetic mechanisms that regulate this metabolic program. I have found that a developmentally-regulated metabolic switch occurs prior to the onset of juvenile growth, consisting of the coordinate up-regulation of glycolysis, the pentose phosphate pathway, and lactate production-a metabolic signature indicative of aerobic glycolysis. I propose to use this programmed developmental event as a model system for dissecting the genetic mechanisms that promote aerobic glycolysis. My initial studies have already proven successful, as I have identified the Drosophila Estrogen- Related Receptor (dERR) as a critical regulator of this metabolic switch. Using a bioinformatics approach, I will determine how coordinate changes in the expression of metabolic genes establish aerobic glycolysis and prepare animals for rapid growth. I will also determine how the timing of dERR protein accumulation and activation triggers the metabolic switch to aerobic glycolysis. Additionally, I will follow up on observations in cancer cells, which have shown that the onset of aerobic glycolysis is accompanied by altered roles for mitochondrial enzymes favoring biosynthetic pathways. I hypothesize that these alterations in mitochondrial activity prepare cellular metabolism for efficient biomass production. I will characterize these changes and determine how mitochondrial metabolism is coordinated with aerobic glycolysis and developmental growth. Once juvenile growth is complete, Drosophila again switches metabolic states to become reliant on fatty acid metabolism. I will explore this second metabolic transition by characterizing the conserved genetic mechanisms that terminate aerobic glycolysis-a critical distinction between normal developmental growth and cancer. These studies will allow, for the first time, a genetic dissection of the mechanisms regulating aerobic glycolysis within the context of normal animal development, and will potentially uncover novel approaches to control cellular growth at a metabolic level.